Manidipine, chemically described as 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl methyl ester is a dihydropyridine calcium channel blocker. It is also known as franidipine and represented by the structure (I) shown below.

Manidipine is a lipophilic and highly vasoselective agent and has long-lasting activity for the treatment of hypertension. Manidipine is a dihydropyridine (DHP) calcium channel antagonist, which effectively reduces blood pressure in patients with mild-to-moderate hypertension and effectively maintains reduced blood pressure levels throughout the dosing period of 24-hours. It is effective in the long term with no evidence of intolerance. Manidipine provides a first-line option for lowering blood pressure in patients with mild-to-moderate hypertension.
The preparation of manidipine and its existence in polymorphic forms is described in EP0094159B1 and its equivalent U.S. Pat. No. 4,892,875. Also, Chem. Pharm. Bull., 1989, 37, (8), 2225-8 describes the synthesis of enantiomeric (+)- and (−)-manidipine dihydrochlorides by esterification of optically active monocarboxylic acids.
Chem. Pharm. Bull., 1985, 33, (9), 3787-3797 discloses two crystalline forms of manidipine dihydrochloride: the α form and the β form, characterized by melting points.
Further, the literature data also shows that manidipine can exist in crystalline base as well as manidipine dihydrochloride monohydrate forms.
Eur J. Med. Chem., 33, 1998, 399-420 discloses manidipine, but gives no characterisation data.
FR 2924223 discloses a method of determine polymorphic purity of manidipine dihydrochloride using Raman spectra. This can be used to prepare manidipine dihydrochoride having predetermined polymorphic purity.
Consequently, it would be a significant contribution to the art to provide a crystalline form of manidipine and pharmaceutically acceptable salts thereof; having increased solubility, and methods of preparation, pharmaceutical formulations, and methods of use thereof.